Jun-ichi Saitoh

Treatment results of radiotherapy for malignant lymphoma of the orbit and histopathologic review according to the WHO classification

PURPOSE To analyze the results of radiotherapy (RT) for malignant lymphoma of the orbit and to evaluate them compared with the World Health Organization (WHO) classification published in 2001. METHODS AND MATERIALS The data from 29 patients with malignant lymphoma of the orbit treated with RT at Gunma University Hospital between 1978 and 2001 were retrospectively analyzed. Pathologic slides from 23 cases were available and were reviewed by a hematopathologist according to the WHO classification. The original and reviewed diagnoses, patient characteristics, treatment results, and complications were analyzed. In principle, patients with low-grade or indolent lymphoma were treated with RT alone, using 30 Gy as the tumor dose. Survival data were calculated using the Kaplan-Meier method. RESULTS One case that proved to be a pseudotumor was excluded from evaluation. Of the 28 cases, 25 were Stage IAE, 1 was Stage IIAE, and 2 were Stage IVAE. The median follow-up was 71 months. According to the original classification and the Working Formulation, the 5- and 10-year overall survival rate of patients with low-grade lymphoma was 94% and 73%, respectively. The corresponding rates for those with intermediate-grade lymphoma were 67% and 67% (p = 0.15). In contrast, the WHO classification showed a significant difference in the survival curves. The 5- and 10-year overall survival rate of patients with mucosa-associated lymphoid tissue (MALT) lymphoma was 100% and 88%, respectively; for diffuse large B-cell patients, the rates were both 0% (p < 0.001). In patients with MALT lymphoma, one local and four distant relapses developed; two of them >10 years after initial treatment. All of the relapsed MALT lymphomas were controlled by salvage therapy. CONCLUSION Excellent local control and survival can be achieved for patients with orbital MALT lymphoma using RT alone. A precise histopathologic diagnosis using the WHO classification and long-term follow-up for >10 years is recommended.

Effect of hyperthermia combined with external radiation therapy in primary non-small cell lung cancer with direct bony invasion

Purpose : Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated. Materials and methods : Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60-70Gy was administered to both groups. Hyperthermia was performed for 45-60min immediately after irradiation for two-four sessions with radiofrequency capacitive heating devices. Results : For primary response, 10 of the 13 tumours responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumours responded (1 CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumours histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical M 0 patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.4%, respectively. No severe pulmonary complication was observed in either group. Conclusions : Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.

Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p53-independent manner

The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines with a different p53 status were investigated. A reduction of radiation-induced G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines. The reduction of survival was observed in a combination of radiation and 2 mM caffeine only in a lower radiation dose range, but not in a higher dose range in NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in a higher dose range for cells with a mutant-type p53. Apoptosis, which was not prominent after irradiation alone or caffeine treatment alone, was induced by irradiation in combination with caffeine in cells with a mutant-type p53 through a p53-independent pathway.

Three-fraction CyberKnife radiotherapy for brain metastases in critical areas: referring to the risk evaluating radiation necrosis and the surrounding brain volumes circumscribed with a single dose equivalence of 14 Gy (V14)

The efficacy and toxicity of three-fraction CyberKnife radiotherapy were evaluated in patients with brain metastases in critical areas. One hundred and fifty-nine metastases in 145 patients including tumors >10 cm3 were treated with three-fraction CyberKnife radiotherapy with a median marginal dose of 27 Gy at a median prescribed isodose of 60%. Changes in the neurological manifestations, local tumor control and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 23.1 Gy (single dose equivalence of 14 Gy: V14) were measured to evaluate the risk of adverse effects. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 26 of 97 patients (26.8%). Local tumor control was obtained in 137 of 143 metastases (95.8%) during a median follow-up of 7 months. Nine patients had symptomatic edema and three of them (2.1%) required surgical resection because of radiation necrosis. The V14 of these patients was 4.6–31.5 cm3. There were 35 lesions with a V14 of 7 cm3 or more and three of them developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7 cm3 exhibited edema requiring an operation. We therefore conclude that a high rate of local tumor control and low rates of complications are obtained after three-fraction CyberKnife radiotherapy for metastases in critical areas. The V14 of the surrounding brain therefore seems to be a useful indicator for the risk evaluation of radiation necrosis in patients with larger metastases.

Therapeutic Effect of Linac-based Stereotactic Radiotherapy with a Micro-multileaf Collimator for the Treatment of Patients with Brain Metastases from Lung Cancer

OBJECTIVE To assess the efficacy of hypofractionated linac-based stereotactic radiotherapy with a micro-multileaf collimator (mMLC) in lung cancer patients with brain metastases. METHODS Seventy-eight lesions of brain metastases in 49 lung cancer patients treated by stereotactic radiotherapy between September 2003 and December 2006 were analyzed. In the treatment planning, the planning target volume (PTV) was defined as an enhanced lesion plus 3 mm margin. A total dose of 39-42 Gy in three fractions was delivered to the isocenters of the PTV. RESULTS The median survival time after stereotactic radiotherapy was 17.4 months. The 1- and 2-year survival rates were 61% and 32%, respectively. The presence of extracranial tumors, the pre-treatment performance status, and the Radiation Therapy Oncology Group recursive partitioning analysis class were significant prognostic factors. The 1- and 2-year local recurrence rates were 14% and 17%, respectively, with no serious acute toxic effect. Injuries involving brain necrosis were observed in six patients. New brain metastases or meningeal carcinomatosis was seen in more than half of the patients following treatment with stereotactic radiotherapy. CONCLUSIONS Hypofactionated stereotactic radiotherapy with mMLC is considered to be an effective and safe modality for the treatment of brain metastases in lung cancer patients.

Correlations between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by β-D-iodinated azomycin galactopyranoside (β-D-IAZGP), and radiation sensitivity ☆

PURPOSE The purpose of this study is to evaluate the amount of hypoxic fraction in a rodent tumor by means of polarographic oxygen electrode, phosphorus-31 magnetic resonance spectroscopy (31P-MRS), and a newly synthesized hypoxic marker, beta-D-iodinated azomycin galactopyranoside (beta-D-IAZGP). We also investigated the radiosensitivity for tumors of different weights. METHODS AND MATERIALS Murine mammary carcinoma cells, FM3A, were subcutaneously implanted into the back of 5-week-old male C3H/He mice. beta-D-IAZGP radiolabeled with 123I or with 125I was injected intravenously into tumor-bearing mice, and marker distribution was measured by nuclear medicine procedures. Radiosensitivity of the tumor was measured by the in vivo/in vitro clonogenic assay. Tumor oxygenation status was also measured directly by polarographic oxygen electrodes and indirectly estimated from 31P-MR spectra. RESULTS Higher accumulation of 123I-beta-D-IAZGP was observed in the tumors than in normal tissues at 24 h after administration. As to biodistribution of 125I-beta-D-IAZGP, the tumor/blood ratio varied widely, but correlated significantly with tumor weight. Mean oxygen pressure (pO2) values and ratios of nucleoside triphosphate beta to inorganic phosphate (beta-ATP/Pi) and of phosphocreatine to inorganic phosphate (PCr/Pi) decreased significantly with the increase in tumor volume. As tumor volume increased, the surviving fraction of cells from tumors irradiated in vivo increased significantly. CONCLUSIONS The increase in tumor volume was significantly correlated with a reduction in mean pO2, a decrease in the ratios of beta-ATP/Pi or PCr/Pi, an increase in uptake of beta-D-IAZGP, and an increase in radioresistance. Because the uptake of beta-D-IAZGP can be measured noninvasively by nuclear medicine techniques, it could be clinically useful for monitoring hypoxia in human tumors.

Phase II study of oral S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer

PURPOSE To determine the efficacy and safety of oral S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS S-1 (50mg/m(2)) was administered orally twice daily for 14 days, with cisplatin (40 mg/m(2)) on days 1 and 8 of each cycle every 3 weeks, for 2-4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. RESULTS Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8-97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. CONCLUSIONS The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC.

Five-fraction CyberKnife radiotherapy for large brain metastases in critical areas: impact on the surrounding brain volumes circumscribed with a single dose equivalent of 14 Gy (V14) to avoid radiation necrosis

The efficacy and toxicity of five-fraction CyberKnife radiotherapy were evaluated in patients with large brain metastases in critical areas. A total of 85 metastases in 78 patients, including tumors >30 cm3 (4 cm in diameter) were treated with five-fraction CyberKnife radiotherapy with a median marginal dose of 31 Gy at a median prescribed isodose of 58%. Changes in the neurological manifestations, local tumor control, and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 28.8 Gy (single dose equivalent to 14 Gy: V14) were measured to evaluate the risk of radiation necrosis. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 28 of 55 patients (50.9%). Local tumor control was obtained in 79 of 85 metastases (92.9%) during a median follow-up of eight months. Symptomatic edema occurred in 10 patients, and two of them (2.6%) required surgical resection because of radiation necrosis. The V14 of these patients was 3.0–19.7 cm3. There were 16 lesions with a V14 of ≥7.0 cm3, and two of these lesions developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7.0 cm3 exhibited edema requiring surgical intervention. We therefore conclude that a high rate of local tumor control and low rates of complications can be obtained after five-fraction CyberKnife radiotherapy for large metastases in critical areas. The V14 of the surrounding brain is therefore a useful indicator for the risk of radiation necrosis in patients with large metastases.

Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors.

Purpose To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. Methods Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. Results The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. Conclusions The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM.

Use of FDG-PET in Radiation Treatment Planning for Thoracic Cancers

Radiotherapy plays an important role in the treatment for thoracic cancers. Accurate diagnosis is essential to correctly perform curative radiotherapy. Tumor delineation is also important to prevent geographic misses in radiotherapy planning. Currently, planning is based on computed tomography (CT) imaging when radiation oncologists manually contour the tumor, and this practice often induces interobserver variability. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to enable accurate staging and detect tumor extension in several thoracic cancers, such as lung cancer and esophageal cancer. FDG-PET imaging has many potential advantages in radiotherapy planning for these cancers, because it can add biological information to conventional anatomical images and decrease the inter-observer variability. FDG-PET improves radiotherapy volume and enables dose escalation without causing severe side effects, especially in lung cancer patients. The main advantage of FDG-PET for esophageal cancer patients is the detection of unrecognized lymph node or distal metastases. However, automatic delineation by FDG-PET is still controversial in these tumors, despite the initial expectations. We will review the role of FDG-PET in radiotherapy for thoracic cancers, including lung cancer and esophageal cancer.